Viren Jain

Charlotte Bunne, Yusuf Roohani, Yanay Rosen et al.

The cell is arguably the most fundamental unit of life and is central to understanding biology. Accurate modeling of cells is important for this understanding as well as for determining the root causes of disease. Recent advances in artificial intelligence (AI), combined with the ability to generate large-scale experimental data, present novel opportunities to model cells. Here we propose a vision of leveraging advances in AI to construct virtual cells, high-fidelity simulations of cells and cellular systems under different conditions that are directly learned from biological data across measurements and scales. We discuss desired capabilities of such AI Virtual Cells, including generating universal representations of biological entities across scales, and facilitating interpretable in silico experiments to predict and understand their behavior using virtual instruments. We further address the challenges, opportunities and requirements to realize this vision including data needs, evaluation strategies, and community standards and engagement to ensure biological accuracy and broad utility. We envision a future where AI Virtual Cells help identify new drug targets, predict cellular responses to perturbations, as well as scale hypothesis exploration. With open science collaborations across the biomedical ecosystem that includes academia, philanthropy, and the biopharma and AI industries, a comprehensive predictive understanding of cell mechanisms and interactions has come into reach.

Jan-Matthis Lueckmann, Viren Jain, Michał Januszewski

Constructing mechanistic models of neural circuits is a fundamental goal of neuroscience, yet verifying such models is limited by the lack of ground truth. To rigorously test model discovery, we establish an in silico testbed using neuromechanical simulations of a larval zebrafish as a transparent ground truth. We find that LLM-based tree search autonomously discovers predictive models that significantly outperform established forecasting baselines. Conditioning on sensory drive is necessary but not sufficient for faithful system identification, as models exploit statistical shortcuts. Structural priors prove essential for enabling robust out-of-distribution generalization and recovery of interpretable mechanistic models. Our insights provide guidance for modeling real-world neural recordings and offer a broader template for AI-driven scientific discovery.

Hao Cui, Zahra Shamsi, Gowoon Cheon et al.

Scientific problem-solving involves synthesizing information while applying expert knowledge. We introduce CURIE, a scientific long-Context Understanding,Reasoning and Information Extraction benchmark to measure the potential of Large Language Models (LLMs) in scientific problem-solving and assisting scientists in realistic workflows. This benchmark introduces ten challenging tasks with a total of 580 problems and solution pairs curated by experts in six disciplines - materials science, condensed matter physics, quantum computing, geospatial analysis, biodiversity, and proteins - covering both experimental and theoretical work-flows in science. We evaluate a range of closed and open LLMs on tasks in CURIE which requires domain expertise, comprehension of long in-context information,and multi-step reasoning. While Gemini Flash 2.0 and Claude-3 show consistent high comprehension across domains, the popular GPT-4o and command-R+ fail dramatically on protein sequencing tasks. With the best performance at 32% there is much room for improvement for all models. We hope that insights gained from CURIE can guide the future development of LLMs in sciences. Evaluation code and data are in https://github.com/google/curie

Gary B. Huang, Viren Jain

Feedforward multilayer networks trained by supervised learning have recently demonstrated state of the art performance on image labeling problems such as boundary prediction and scene parsing. As even very low error rates can limit practical usage of such systems, methods that perform closer to human accuracy remain desirable. In this work, we propose a new type of network with the following properties that address what we hypothesize to be limiting aspects of existing methods: (1) a `wide' structure with thousands of features, (2) a large field of view, (3) recursive iterations that exploit statistical dependencies in label space, and (4) a parallelizable architecture that can be trained in a fraction of the time compared to benchmark multilayer convolutional networks. For the specific image labeling problem of boundary prediction, we also introduce a novel example weighting algorithm that improves segmentation accuracy. Experiments in the challenging domain of connectomic reconstruction of neural circuity from 3d electron microscopy data show that these "Deep And Wide Multiscale Recursive" (DAWMR) networks lead to new levels of image labeling performance. The highest performing architecture has twelve layers, interwoven supervised and unsupervised stages, and uses an input field of view of 157,464 voxels ($54^3$) to make a prediction at each image location. We present an associated open source software package that enables the simple and flexible creation of DAWMR networks.

Jan-Matthis Lueckmann, Alexander Immer, Alex Bo-Yuan Chen et al.

Data-driven benchmarks have led to significant progress in key scientific modeling domains including weather and structural biology. Here, we introduce the Zebrafish Activity Prediction Benchmark (ZAPBench) to measure progress on the problem of predicting cellular-resolution neural activity throughout an entire vertebrate brain. The benchmark is based on a novel dataset containing 4d light-sheet microscopy recordings of over 70,000 neurons in a larval zebrafish brain, along with motion stabilized and voxel-level cell segmentations of these data that facilitate development of a variety of forecasting methods. Initial results from a selection of time series and volumetric video modeling approaches achieve better performance than naive baseline methods, but also show room for further improvement. The specific brain used in the activity recording is also undergoing synaptic-level anatomical mapping, which will enable future integration of detailed structural information into forecasting methods.

Alexander Immer, Jan-Matthis Lueckmann, Alex Bo-Yuan Chen et al.

Large-scale neuronal activity recordings with fluorescent calcium indicators are increasingly common, yielding high-resolution 2D or 3D videos. Traditional analysis pipelines reduce this data to 1D traces by segmenting regions of interest, leading to inevitable information loss. Inspired by the success of deep learning on minimally processed data in other domains, we investigate the potential of forecasting neuronal activity directly from volumetric videos. To capture long-range dependencies in high-resolution volumetric whole-brain recordings, we design a model with large receptive fields, which allow it to integrate information from distant regions within the brain. We explore the effects of pre-training and perform extensive model selection, analyzing spatio-temporal trade-offs for generating accurate forecasts. Our model outperforms trace-based forecasting approaches on ZAPBench, a recently proposed benchmark on whole-brain activity prediction in zebrafish, demonstrating the advantages of preserving the spatial structure of neuronal activity.

Kisuk Lee, Jonathan Zung, Peter Li et al.

For the past decade, convolutional networks have been used for 3D reconstruction of neurons from electron microscopic (EM) brain images. Recent years have seen great improvements in accuracy, as evidenced by submissions to the SNEMI3D benchmark challenge. Here we report the first submission to surpass the estimate of human accuracy provided by the SNEMI3D leaderboard. A variant of 3D U-Net is trained on a primary task of predicting affinities between nearest neighbor voxels, and an auxiliary task of predicting long-range affinities. The training data is augmented by simulated image defects. The nearest neighbor affinities are used to create an oversegmentation, and then supervoxels are greedily agglomerated based on mean affinity. The resulting SNEMI3D score exceeds the estimate of human accuracy by a large margin. While one should be cautious about extrapolating from the SNEMI3D benchmark to real-world accuracy of large-scale neural circuit reconstruction, our result inspires optimism that the goal of full automation may be realizable in the future.

David Rolnick, Yaron Meirovitch, Toufiq Parag et al.

Deep learning algorithms for connectomics rely upon localized classification, rather than overall morphology. This leads to a high incidence of erroneously merged objects. Humans, by contrast, can easily detect such errors by acquiring intuition for the correct morphology of objects. Biological neurons have complicated and variable shapes, which are challenging to learn, and merge errors take a multitude of different forms. We present an algorithm, MergeNet, that shows 3D ConvNets can, in fact, detect merge errors from high-level neuronal morphology. MergeNet follows unsupervised training and operates across datasets. We demonstrate the performance of MergeNet both on a variety of connectomics data and on a dataset created from merged MNIST images.

Michał Januszewski, Jeremy Maitin-Shepard, Peter Li et al.

State-of-the-art image segmentation algorithms generally consist of at least two successive and distinct computations: a boundary detection process that uses local image information to classify image locations as boundaries between objects, followed by a pixel grouping step such as watershed or connected components that clusters pixels into segments. Prior work has varied the complexity and approach employed in these two steps, including the incorporation of multi-layer neural networks to perform boundary prediction, and the use of global optimizations during pixel clustering. We propose a unified and end-to-end trainable machine learning approach, flood-filling networks, in which a recurrent 3d convolutional network directly produces individual segments from a raw image. The proposed approach robustly segments images with an unknown and variable number of objects as well as highly variable object sizes. We demonstrate the approach on a challenging 3d image segmentation task, connectomic reconstruction from volume electron microscopy data, on which flood-filling neural networks substantially improve accuracy over other state-of-the-art methods. The proposed approach can replace complex multi-step segmentation pipelines with a single neural network that is learned end-to-end.

Jeremy Maitin-Shepard, Viren Jain, Michal Januszewski et al.

We introduce a new machine learning approach for image segmentation that uses a neural network to model the conditional energy of a segmentation given an image. Our approach, combinatorial energy learning for image segmentation (CELIS) places a particular emphasis on modeling the inherent combinatorial nature of dense image segmentation problems. We propose efficient algorithms for learning deep neural networks to model the energy function, and for local optimization of this energy in the space of supervoxel agglomerations. We extensively evaluate our method on a publicly available 3-D microscopy dataset with 25 billion voxels of ground truth data. On an 11 billion voxel test set, we find that our method improves volumetric reconstruction accuracy by more than 20% as compared to two state-of-the-art baseline methods: graph-based segmentation of the output of a 3-D convolutional neural network trained to predict boundaries, as well as a random forest classifier trained to agglomerate supervoxels that were generated by a 3-D convolutional neural network.

John A. Bogovic, Gary B. Huang, Viren Jain

For image recognition and labeling tasks, recent results suggest that machine learning methods that rely on manually specified feature representations may be outperformed by methods that automatically derive feature representations based on the data. Yet for problems that involve analysis of 3d objects, such as mesh segmentation, shape retrieval, or neuron fragment agglomeration, there remains a strong reliance on hand-designed feature descriptors. In this paper, we evaluate a large set of hand-designed 3d feature descriptors alongside features learned from the raw data using both end-to-end and unsupervised learning techniques, in the context of agglomeration of 3d neuron fragments. By combining unsupervised learning techniques with a novel dynamic pooling scheme, we show how pure learning-based methods are for the first time competitive with hand-designed 3d shape descriptors. We investigate data augmentation strategies for dramatically increasing the size of the training set, and show how combining both learned and hand-designed features leads to the highest accuracy.